title: Asymmetric chemoenzymatic synthesis of miconazole and econazole enantiomers. The importance of chirality in their biological evaluation.
abstract: A simple and novel chemoenzymatic route has been applied for the first time in the synthesis of miconazole and econazole single enantiomers. Lipases and oxidoreductases have been tested in stereoselective processes; the best results were attained with oxidoreductases for the introduction of chirality in an adequate intermediate. The behaviors of a series of ketones and racemic alcohols in bioreductions and acetylation procedures, respectively, have been investigated; the best results were found with alcohol dehydrogenases A and T, which allowed the production of (R)-2-chloro-1-(2,4-dichlorophenyl)ethanol in enantiopure form under very mild reaction conditions. Final chemical modifications have been performed in order to isolate the target fungicides miconazole and econazole both as racemates and as single enantiomers. Biological evaluation of the racemates and single enantiomers has shown remarkable differences against the growth of several microorganisms; while (R)-miconazole seemed to account for most of the biological activity of racemic miconazole on all the strains tested, both enantiomers of econazole showed considerable biological activities. In this manner, (R)-econazole showed higher values against Candida krusei , while higher values were observed for (S)-econazole against Cryptococcus neoformans, Penicillium chrysogenum, and Aspergillus niger.
authors.affiliation: Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Mangas-Sánchez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Busto
authors.forename: Vicente
authors.initials: V
authors.lastname: Gotor-Fernández
authors.forename: Francisco
authors.initials: F
authors.lastname: Malpartida
authors.forename: Vicente
authors.initials: V
authors.lastname: Gotor
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002175:Candida / Q000737:chemistry / Q000187:drug effects; D004464:Econazole / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000138:chemical synthesis* / Q000737:chemistry*; D008049:Lipase / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008825:Miconazole / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: C561069:(R)-2-chloro-1-(2,4-dichlorophenyl)ethanol; D000935:Antifungal Agents; D006843:Hydrocarbons, Chlorinated; D004464:Econazole; D008825:Miconazole; D008049:Lipase